Toward the rational development of peptidomimetic analogs of the C-terminal endothelin hexapeptide: development of a theoretical model

In an early report on the structure-activity relationship of endothelin (ET ) peptides, it was reported that the C-terminal hexapeptide ET(16-21), His- Leu-Asp-Ile-Ile-Trp, is the minimum ET fragment which maintains biological activity in some, but not all the tissues responding to ETs. Subsequently, other authors described a series of analogs of this peptide, in which the H is16 residue was replaced by non-natural amino acids, characterized by bulk y aromatic side chains. Among them, two well-characterized non-selective ET A/ETB antagonists were PD 142893 and PD 145065; interest in these potent ET antagonists was, however, reduced by their peptidic structure which was li kely to lead to undesirable properties such as poor bioavailability and sho rt duration of action. On the basis of these premises, our previous studies led to the development of a peptidomimetic ligand of ET receptors (compoun d 3), based on the replacement of the His16 residue of ET(16-21) with an (E )-N-(benzyloxy)iminoacyl moiety; compound 3 proved to possess a certain aff inity for ET receptors, albeit lower than that shown by PD 142893 and PD 14 5065. We report here on ETA/ETB binding affinity of compounds 4-12, designe d as a new series of ET(16-21) analogs. Compounds 4 and 5 were practically devoid of any affinity; derivatives 6-12 exhibited appreciable affinity ind ices for ETB receptors higher than that shown by 3, even if still lower tha n that obtained for PD 145065. This paper also describes the development of a pharmacophoric model able to explain the ET receptor binding properties of our hexapeptide analogs compared with those of PD 142893 and PD 145065 a nd IRL2500, recently reported as a potent ETB selective endothelin antagoni st. (C) 1998 Elsevier Science S.A. All rights reserved.